Chronic administration of cannabinoid agonists ACEA (CB1), AM1241 (CB2), and CP55,940 (mixed CB1/CB2) induce sex-specific differences in tolerance and sex hormone changes in a chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term anti-allodynic efficacy of CB1-selective (ACEA), CB2-selective (AM1241), and CB1/CB2 mixed (CP55,940) agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to anti-allodynic effects, with females developing tolerance more rapidly than males, while the anti-allodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. Significance Statement CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB¬2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB¬2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB¬2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.

Open and Robotic Uretero-enteric Stricture Repair: Early Outcomes and Complications.

Objective: To characterize our single institutional experience with robotic and open uretero-enteric stricture (UES) repair. Materials and Methods: We queried our ureteral reconstructive database for UES repair between 01/2017 and 10/2023. Patients with <3 months follow-up were excluded. Prior to surgery, patients underwent ureteral rest (4 weeks) with conversion to nephrostomy tube. Clinical characteristics, complications, reconstructive success (uretero-enteric patency), need for repeat intervention, and renal function were assessed in patients undergoing open and robotic UES reconstruction. Results: Of 50 patients undergoing UES repair during the study period, 45 were included for analysis due to complete follow-up (34 [76%] robotic and 11 [24%] open repair). UES repair was performed in 50 renal units a median of 13 months (interquartile range 7-30) from index surgery, and most often involved the left renal unit (34/50; 68%). Compared with robotic, open cases were significantly more likely to have undergone open cystectomy (100% vs 68%, p = 0.04), have longer strictures (median 4 vs 1 cm, p < 0.001), require tissue substitution (27% vs 3%, p = 0.04), and have lengthier postoperative hospitalization (5 vs 2 days, p < 0.001). There was no significant difference in total operative time (410 vs 322 minutes) or 30d major complications (18% vs 21%). At a follow-up of 13 months, per patient reconstructive success was 100% (11/11) for open and 97% (33/34) for robotic, respectively. Conclusion: In select patients with short UES unlikely to require advanced reconstructive techniques, a robotic-assisted approach can be considered. Careful patient selection is associated with limited morbidity and high reconstructive success.

High Rates of Discordant Ureteral Perfusion During Open Ureteral Reconstruction With Indocyanine Green: Does Near-Infrared Fluorescence Imaging Change Management or Stricture Outcomes?

OBJECTIVE: To determine the role of near-infrared fluorescence imaging (NIFI) combined with indocyanine green (ICG) to assess ureteral tissue perfusion in a benign genitourinary reconstruction cohort with a high prevalence of prior abdominopelvic radiation and surgery. MATERIALS AND METHODS: A prospective, single-surgeon series, between June 2018 and April 2022, of patients who underwent open genitourinary reconstructive surgeries in which NIFI/ICG was utilized to intraoperatively assess ureteral tissue perfusion prior to ureteral anastomosis. Primary outcome was ureteroanastomotic stricture (UAS). Secondary outcomes included impact of NIFI/ICG on surgical decision-making and ureter resection length. RESULTS: Thirty nine patients, median age 66, underwent 40 multimodality reconstructive surgeries during which NIFI/ICG was utilized in the open setting. Radiation-induced etiology was present in 32 of 40 (80%) patients. UAS occurred in 1 of 57 (1.8%) anastomoses with median follow-up of 23.4 months. Use of NIFI/ICG changed intraoperative decision-making in 63% of cases. Change in intraoperative decision-making was more common in patients with prior abdominopelvic radiation (66%) compared to non-radiated patients (13%), P = .007. Discordance between subjective (white-light) and objective (NIFI/ICG) ureteral perfusion (white-light) occurred in 61% of ureters. Mean length of resected ureter was higher following objective assessment with NIFI/ICG (3.6 cm) versus subjective assessment (white light) conditions (1.8 cm), P = .001. CONCLUSION: Use of NIFI/ICG was associated with low rates of UAS at 2-year follow-up in a cohort with high prevalence of prior radiation. NIFI/ICG was associated with longer lengths of ureter resection and ureteral perfusion assessment discordance compared to subjective surgeon assessment under white-light conditions.

Randomised controlled trial of an online cognitive training program in school-aged children with cerebral palsy.

BACKGROUND: Children with cerebral palsy (CP) experience deficits in nonverbal reasoning. The SMART online cognitive intervention has been associated with gains in IQ and nonverbal IQ in previous studies in typically developing school-aged children and children experiencing learning difficulties. AIM: To assess the efficacy of an online cognitive intervention in school-aged children with CP. METHODS AND PROCEDURES: 21 children with CP (male n = 17; 76.2%), mean age 9 y 8 m, SD 1 y 1 month (range 8 y 3 m to 12 y 6 m) were randomised into the intervention group (n = 9) or a waitlist control group. A mixed-methods approach with an explanatory sequential design was used, with a randomised controlled trial followed by qualitative interviews. Participants were assessed on measures of intelligence, academic ability, attention and executive functioning, and social-emotional functioning at baseline, then after completing the training, or the waitlist period. Analyses included ANCOVAs and paired samples t tests. Semi-structured interviews explored participants' experiences with the training. RESULTS AND OUTCOMES: Training completion was low with a mean of 16.9 modules completed out of 55 available. No significant effect of training was found for the primary outcome of intelligence, or for any secondary outcomes. Participants reported barriers and facilitators for accessing the program. IMPLICATIONS: Cognitive training programs addressing relational framing ability may require significant modifications before they can be effectively tested with children with CP.

Evaluation of an Opioid-free Pathway for Perineal Reconstructive Surgery: A 1-year Pilot Study.

OBJECTIVE: To evaluate the impact of a standardized perioperative pain management pathway on postoperative opioid prescribing practices following male perineal reconstructive surgery at our institution. METHODS: Patients undergoing perineal reconstructive surgery (urethroplasty, artificial urinary sphincter, urethral sling) by a single surgeon from July 2022 to June 2023 were prospectively followed. A standardized nonopioid pathway was implemented in the perioperative period. Intraoperative local anesthetic included liposomal bupivacaine mixed with 0.25% bupivacaine. Opioids are administered in the recovery room at the discretion of anesthesiology providers. As of July 2022, our standard practice does not include a postoperative opioid prescription unless pain is poorly controlled in the recovery area. Postoperative communication encounters and opioid prescriptions were tracked through the electronic health record (EHR) in order to assess the efficacy of an opioid-free pathway. RESULTS: Sixty-seven patients met the criteria during the study period, 64/67 performed in an outpatient setting. 6/67 (9%) patients were prescribed an opioid postoperatively; 4 related to post-surgical pain, and 2 related to chronic pain. No refills were prescribed. Of the 26 patients who received an opioid in the recovery area, 2 (7.6%) were prescribed an opioid at discharge. 15/67 (22%) patients had a communication encounter related to pain within 30 days, most commonly related to bladder spasm management. Only 2 of these encounters resulted in an electronic opioid prescription. CONCLUSION: An opioid-free pathway is appropriate for opioid naive men undergoing perineal reconstructive surgery. When necessary, electronic opioid prescribing should be employed following discharge for breakthrough pain.

Social evaluative stress enhances central detail memory, reduces false memory, and results in intrusive memories that last for days.

Few studies have quantified what an individual remembers about a laboratory-controlled stressor. Here, we aimed to replicate previous work by using a modified version of the Trier Social Stress Test (TSST) to quantify participant memory for a stressful experience. We also aimed to extend this work by quantifying false and intrusive memories that ensued. One hundred and seven participants were exposed to the TSST (stress) or the friendly TSST (f-TSST; no stress). The TSST required participants to deliver a ten-minute speech in front of two laboratory panel members as part of a mock job interview; the f-TSST required participants to casually converse with the panel members about their interests. In both conditions, the panel members interacted with (central) or did not interact with (peripheral) several objects sitting on a desk in front of them. The next day, participants' memory for the objects was assessed with recall and recognition tests. We also quantified participants' intrusive memories on Days 2, 4, 6, and 8. Stressed participants recalled more central objects and exhibited greater recognition memory, particularly for central objects, than controls. Stress also led to less false recall and more intrusive memories on Days 2 and 4. Consistent with previous work, these findings suggest that participants exhibit enhanced memory for the central details of a stressful experience; they also extend prior work by showing that participants exposed to a stressor have less false memories and experience intrusive memories for several days following the event. The modified TSST paradigm used here may be useful for researchers studying not only what participants remember about a stressful event but also their susceptibility to intrusive memory formation.

Supplementation of vitamin E or a botanical extract as antioxidants to improve growth performance and health of growing pigs housed under thermoneutral or heat-stressed conditions.

BACKGROUND: Heat stress has severe negative consequences on performance and health of pigs, leading to significant economic losses. The objective of this study was to investigate the effects of supplemental vitamin E and a botanical extract in feed or drinking water on growth performance, intestinal health, and oxidative and immune status in growing pigs housed under heat stress conditions. METHODS: Duplicate experiments were conducted, each using 64 crossbred pigs with an initial body weight of 50.7 ± 3.8 and 43.9 ± 3.6 kg and age of 13-week and 12-week, respectively. Pigs (n = 128) were housed individually and assigned within weight blocks and sex to a 2 × 4 factorial arrangement consisting of 2 environments (thermo-neutral (21.2 °C) or heat-stressed (30.9 °C)) and 4 supplementation treatments (control diet; control + 100 IU/L of D-α-tocopherol in water; control + 200 IU/kg of DL-α-tocopheryl-acetate in feed; or control + 400 mg/kg of a botanical extract in feed). RESULTS: Heat stress for 28 d reduced (P ≤ 0.001) final body weight, average daily gain, and average daily feed intake (-7.4 kg, -26.7%, and -25.4%, respectively) but no effects of supplementation were detected (P > 0.05). Serum vitamin E increased (P < 0.001) with vitamin E supplementation in water and in feed (1.64 vs. 3.59 and 1.64 vs. 3.24), but not for the botanical extract (1.64 vs. 1.67 mg/kg) and was greater when supplemented in water vs. feed (P = 0.002). Liver vitamin E increased (P < 0.001) with vitamin E supplementations in water (3.9 vs. 31.8) and feed (3.9 vs. 18.0), but not with the botanical extract (3.9 vs. 4.9 mg/kg). Serum malondialdehyde was reduced with heat stress on d 2, but increased on d 28 (interaction, P < 0.001), and was greater (P < 0.05) for antioxidant supplementation compared to control. Cellular proliferation was reduced (P = 0.037) in the jejunum under heat stress, but increased in the ileum when vitamin E was supplemented in feed and water under heat stress (interaction, P = 0.04). Tumor necrosis factor-α in jejunum and ileum mucosa decreased by heat stress (P < 0.05) and was reduced by vitamin E supplementations under heat stress (interaction, P < 0.001). CONCLUSIONS: The addition of the antioxidants in feed or in drinking water did not alleviate the negative impact of heat stress on feed intake and growth rate of growing pigs.

Sacral insufficiency fractures are a frequent and painful consequence of pubic symphysis osteomyelitis.

BACKGROUND: Pubic symphysis osteomyelitis can result from urosymphyseal fistula formation. High rates of sacropelvic insufficiency fractures have been reported in this population. The aim of this study was to describe the presentation and risk factors for sacral insufficiency fractures (SIF) associated with surgical treatment of pubic symphysis osteomyelitis. METHODS: A retrospective review was performed for 54 patients who underwent surgery for pubic symphysis osteomyelitis associated with a urosymphyseal fistula at a single institution from 2009 to 2022. Average age was 71 years and 53 patients (98%) were male. All patients underwent debridement or partial resection of the pubic symphysis at the time of fistula treatment. Average width of the symphyseal defect was 65 mm (range 9-122) after treatment. RESULTS: Twenty patients (37%) developed SIF at a mean time of 4 months from osteomyelitis diagnosis. Rate of sacral fracture on Kaplan-Meier analysis was 31% at 6 months, 39% at 12 months, and 41% at 2 years. Eleven patients developed SIF prior to pubic debridement and 12 patients developed new or worsening of pre-existing SIF following surgery. Width of pubic resection was higher in patients who developed SIF (76 mm vs. 62 mm), but this did not meet statistical significance (p = 0.18). CONCLUSION: Sacral insufficiency fracture is a common sequela of pubic symphysis osteomyelitis. These fractures are often multifocal within the pelvis and can occur even prior to pubic resection. Pubectomy further predisposes these patients to fracture. Clinicians should maintain a high index of suspicion for these injuries in patients with symphyseal osteomyelitis.

Predictors of Excellent Urology Residents at the Time of the Urology Match.

OBJECTIVE: To update our experience and report on features predictive of high-quality urology residents at the time of the urology match, because data predicting which medical students will mature into excellent urology residents are sparse. METHODS: We reviewed our experience with 84 urology residents who graduated from 2006 to 2023. Residents were independently scored 1-10 based on overall quality by the current and former Program Director. Discrepant scoring by >2 was resolved by an independent review. Associations of features from the medical student application with an excellent score (defined as 8-10) were evaluated with logistic regression. RESULTS: Discrepant scoring >2 was noted in only 5 (6%) residents. Among the 84 residents, the median overall score was 7 (range 1-10) and 36 (43%) residents had an excellent score of 8-10. Univariably, higher USMLE step II score (P = .03), election to alpha omega alpha (P = .004), no negative interview comments (P = .002), honors in OB/Gyn (P = .048) and psychiatry clerkships (P = .04), and honors in all core clinical clerkships (P < .001) were significantly associated with an excellent score. In a multivariable model, no negative interview comments (P = .003) and honors in all core clinical clerkships (P = .001) were independently associated with an excellent score (c-index 0.76). There were several notable features (sex, letters of recommendation, USMLE step I, externship at our institution, surgery clerkship grade, and rank list) that were not significantly associated with excellent residents. CONCLUSION: We demonstrate features associated with excellent urology residents, most notably no negative interview comments and an honors grade in all core clinical clerkships.

Constructing validity evidence from a pilot key-features assessment of clinical decision-making in cerebral palsy diagnosis: application of Kane's validity framework to implementation evaluations.

BACKGROUND: Physician decision-making skills training is a priority to improve adoption of the cerebral palsy (CP) clinical guideline and, through this, lower the age of CP diagnosis. Clinical guideline implementation aims to improve physician practice, but evaluating meaningful change is complex. Limitations in the validity evidence of evaluation instruments impact the evidence base. Validity frameworks, such as Kane's, enable a targeted process to gather evidence for instrument scores, congruent to context and purpose. Yet, application of argument-based methodology to implementation validation is rare. Key-features examination methodology has established validity evidence supporting its use to measure decision-making skills, with potential to predict performance. We aimed to apply Kane's framework to evaluate a pilot key-features examination on physician decision-making in early CP diagnosis. METHODS: Following Kane's framework, we evaluated evidence across inferences of scoring, generalisation, extrapolation and implications in a study design describing the development and pilot of a CP diagnosis key-features examination for practising physicians. If found to be valid, we proposed to use the key-feature scores as an outcome measure of decision-making post education intervention to expedite CP diagnosis and to correlate with real-world performance data to predict physician practice. RESULTS: Supporting evidence for acceptance of scoring inferences was achieved through examination development with an expert group (n = 10) and pilot results (n = 10): (1) high internal consistency (0.82); (2) acceptable mean item-discrimination (0.34); and (3) acceptable reliability of examination scorers (95.2% congruence). Decreased physician acceptance of examination time (70%) was identified as a threat and prioritised in case reduction processes. Partial acceptance of generalisation, extrapolation and implications inferences were defensible with: (1) accumulated development evidence following established key-features methodology; (2) high pilot acceptance for authenticity (90%); and (3) plausibility of assumptions of score correlation with population register data. CONCLUSIONS: Kane's approach is beneficial for prioritising sources of validity evidence alongside the iterative development of a key-features examination in the CP field. The validity argument supports scoring assumptions and use of scores as an outcome measure of physician decision-making for CP guideline education implementation interventions. Scoring evidence provides the foundation to direct future studies exploring association of key-feature scores with real-world performance.

Role of Cannabinoid Signaling in Cardiovascular Function and Ischemic Injury.

Cardiovascular disease represents a leading cause of death, morbidity, and societal economic burden. The prevalence of cannabis use has significantly increased due to legalization and an increased societal acceptance of cannabis. Therefore, it is critically important that we gain a greater understanding of the effects and risks of cannabinoid use on cardiovascular diseases as well as the potential for cannabinoid-directed drugs to be used as therapeutics for the treatment of cardiovascular disease. This review summarizes our current understanding of the role of cannabinoid receptors in the pathophysiology of atherosclerosis and myocardial ischemia and explores their use as therapeutic targets in the treatment of ischemic heart disease. Endocannabinoids are elevated in patients with atherosclerosis, and activation of cannabinoid type 1 receptors (CB1Rs) generally leads to an enhancement of plaque formation and atherosclerosis. In contrast, selective activation of cannabinoid type 2 receptors (CB2Rs) appears to exert protective effects against atherosclerosis. Endocannabinoid signaling is also activated by myocardial ischemia. CB2R signaling appears to protect the heart from ischemic injury, whereas the role of CB1R in ischemic injury is less clear. This narrative review serves to summarize current research on the role of cannabinoid signaling in cardiovascular function with the goal of identifying critical knowledge gaps and future studies to address those gaps in a way that facilitates the development of new treatments and better cardiovascular health. SIGNIFICANCE STATEMENT: Cardiovascular diseases, including atherosclerosis and myocardial infarction, are a leading cause of death. Cannabinoid drugs have well known acute effects on cardiovascular function, including tachycardia and orthostatic hypotension. The recent legalization of marijuana and cannabinoids for both medical and recreational use has dramatically increased their prevalence of use. This narrative review on the role of cannabinoid signaling in cardiovascular disease contributes to a better understanding of this topic by integrating current knowledge and identifying critical gaps.

Genitourinary Radiation Injury Following Prostate Cancer Treatment: Assessment of Cost and Health Care System Burden.

OBJECTIVE: To evaluate the healthcare resource impact of radiation injury following prostate cancer treatment. METHODS: Using IBM MarketScan, we performed a retrospective study of men with prostate cancer who were treated with radiotherapy and subsequently developed low-grade (LGRI) and high-grade radiation injury (HGRI). Radiation injury diagnoses included bladder neck stenosis, hematuria/cystitis, fistula, ureteral stricture, and incontinence. LGRI and HGRI included injury diagnosis without intervention and with intervention, respectively. Health care visits and costs were measured over 5 time periods including 2 years before radiation, 1 year before radiation, radiation to injury diagnosis, injury diagnosis to first intervention (LGRI), and following first intervention (HGRI). Negative binomial regression modeling was used to assess the effect of radiation injury on average cost adjusting for demographics and comorbidities. RESULTS: Between 2008 and 2017, we identified 121,027 men who received radiotherapy following prostate cancer diagnosis of which 10,057 (8.3%) experienced a HGRI. The frequency of urologic visits and average costs were similar in those without injury and LGRI. However, men with HGRI experienced higher visit frequency and monthly costs. Amongst high-grade injuries, urinary fistula had the highest frequency of visit utilization at 378 visits before first intervention and 245 visits after first intervention. Following radiation injury diagnosis, the average monthly cost was twice as high in those with HGRI ($85.78) compared to LGRI ($38.66). CONCLUSIONS: HGRI was associated with increased urologic health care use and average monthly cost when compared to those who experienced LGRI or no injury. Urinary fistula was associated with the largest resource burden.

Pre-Learning Stress That Is Temporally Removed from Acquisition Impairs Fear Learning.

Few studies have examined the time-dependent effects of stress on fear learning. Previously, we found that stress immediately before fear conditioning enhanced fear learning. Here, we aimed to extend these findings by assessing the effects of stress 30 min prior to fear conditioning on fear learning and fear generalization. Two hundred and twenty-one healthy adults underwent stress (socially evaluated cold pressor test) or a control manipulation 30 min before completing differential fear conditioning in a fear-potentiated startle paradigm. One visual stimulus (CS+), but not another (CS-), was associated with an aversive airblast to the throat (US) during acquisition. The next day, participants were tested for their fear responses to the CS+, CS-, and several generalization stimuli. Stress impaired the acquisition of fear on Day 1 but had no significant impact on fear generalization. The stress-induced impairment of fear learning was particularly evident in participants who exhibited a robust cortisol response to the stressor. These findings are consistent with the notion that stress administered 30 min before learning impairs memory formation via corticosteroid-related mechanisms and may help us understand how fear memories are altered in stress-related psychological disorders.

Characterization of Gender Differences in H-index Within Urological Subspecialties.

PURPOSE: Previous work in urology has shown that men have higher h-indices than women. However, the degree to which h-indices vary by gender within urological subspecialties has not been well defined. Herein, we assess gender differences in h-index among different subspecialties. MATERIALS AND METHODS: Demographics were recorded for academic urologists using residency program websites as of July 2021. Scopus was queried to identify h-indices. Gender differences in h-index were estimated from a linear mixed-effects regression model with fixed effects for gender, urological subspecialty, MD/PhD status, years since first publication, interactions of subspecialty with years since first publication, and interactions of subspecialty with gender and random effects for AUA section and institution nested within AUA section. The Holm method was used to adjust for multiplicity (7 hypothesis tests). RESULTS: Of 1,694 academic urologists from 137 institutions, 308 were women (18%). Median years since first publication was 20 for men (IQR 13, 29) and 13 for women (IQR 8, 17). Among all academic urologists, the median h-index was 8 points higher for men (15 [IQR 7, 27]) vs women (7 [IQR 5, 12]). There was no significant gender difference in h-index for any of the subspecialties after adjusting for urologist experience and after applying the Holm method for multiplicity correction. CONCLUSIONS: We were unable to demonstrate a gender difference in h-index after adjusting for urologist experience for any urological subspecialties. Future study is warranted as women become more senior members of the urological workforce.